Use of S1P Receptor Agonists in Heart Diseases

ABSTRACT

The invention relates to the use of sphingosine-1-phosphate receptor agonist in the treatment of heart diseases.

The present invention relates to a new use for a sphingosine-1-phosphate (S1P) receptor agonist, particularly in the treatment of heart diseases.

S1P receptor agonists are accelerating lymphocyte homing agents which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, without evoking a generalized immunosuppression. Naïve cells are sequestered; CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP), and thus for example infiltration of cells into transplanted organs is inhibited.

S1P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives, e.g. a compound comprising a group of formula X

wherein Z is H; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; phenyl; phenyl substituted by OH; C₁₋₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cyclo-alkyl, phenyl and phenyl substituted by OH; or CH₂—R_(4z) wherein R_(4z) is OH, acyloxy or a residue of formula (a)

wherein Z₁ is a direct bond or O, preferably O; each of R_(5z), and R_(6z), independently, is H, or C₁₋₄alkyl optionally substituted by 1, 2 or 3 halogen atoms; R_(1z) is OH, acyloxy or a residue of formula (a); and each of R_(2z) and R_(3z), independently, is H, C₁₋₄alkyl or acyl.

Group of formula X is a functional group attached as a terminal group to a moiety which may be hydrophilic or lipophilic and comprise one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and R_(1z) is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1-phosphate receptor.

S1P receptor agonists are compounds which signal as agonists at one or more sphingosine-1 phosphate receptors, e.g. S1P1 to S1P8. Agonist binding to a S1P receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins into Gα-GTP and Gβγ-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases. The binding affinity of S1P receptor agonists may be measured as described at paragraph I. below. Preferred S1P receptor agonists are those targeting e.g. S1P2 and/or S1P3.

Examples of appropriate S1P receptor agonists are, for example

-   -   Compounds as disclosed in EP627406A1, e.g. a compound of formula         I

wherein R₁ is a straight- or branched (C₁₂₋₂₂)carbon chain

-   -   which may have in the chain a bond or a hetero atom selected         from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H,         alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or         -   which may have as a substituent alkoxy, alkenyloxy,             alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,             acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,             alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy             or carboxy; or

R₁ is

-   -   a phenylalkyl wherein alkyl is a straight- or branched         (C₆₋₂₀)carbon chain; or     -   a phenylalkyl wherein alkyl is a straight- or branched         (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by     -   a straight- or branched (C₆₋₂₀)carbon chain optionally         substituted by halogen,     -   a straight- or branched (C₆₋₂₀)alkoxy chain optionally         substituted by halogen,     -   a straight- or branched (C₆₋₂₀)alkenyloxy,     -   phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy         or phenoxyalkyl,     -   cycloalkylalkyl substituted by C₆₋₂₀alkyl,     -   heteroarylalkyl substituted by C₆₋₂₀alkyl,     -   heterocyclic C₆₋₂₀alkyl or     -   heterocyclic alkyl substituted by C₂₋₂₀alkyl,         and wherein         the alkyl moiety may have     -   in the carbon chain, a bond or a heteroatom selected from a         double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆,         wherein R₆ is as defined above, and     -   as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy,         acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl,         alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen,         amino, hydroxy or carboxy, and         each of R₂, R₃, R₄ and R₅, independently, is H, C₁₋₄ alkyl or         acyl         or a pharmaceutically acceptable salt thereof;     -   Compounds as disclosed in EP 1002792A1, e.g. a compound of         formula II

wherein m is 1 to 9 and each of R′₂, R′₃, R′₄ and R′₅, independently, is H, alkyl or acyl, or a pharmaceutically acceptable salt thereof;

-   -   Compounds as disclosed in EP0778263 A1, e.g. a compound of         formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted or by OH substituted phenyl; R″₄O(CH₂)_(n); or C₁₋₆-alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p−1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of C₁₋₆ alkyl, OH, C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo, haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3, each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl, or a pharmaceutically acceptable salt thereof,

-   -   Compounds as disclosed in WO02/18395, e.g. a compound of formula         IVa or IVb

wherein X_(a) is O, S, NR_(1s) or a group —(CH₂)_(na)—, which group is unsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s) is H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or (C₁₋₄)alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) is independently selected from H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or (C₄₋₁₄alkenyl; or a pharmaceutically acceptable salt or hydrate thereof;

-   -   Compounds as disclosed in WO 02/076995, e.g. a compound of         formula V

wherein

-   m_(c) is 1, 2 or 3; -   X_(c) is O or a direct bond; -   R_(1c) is H; C₁₋₆ alkyl optionally substituted by OH, acyl, halogen,     C₃₋₁₀cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl;     C₂₋₆alkynyl; or phenyl optionally substituted by OH; -   R_(2c) is

-   -   wherein R_(5c) is H or C₁₋₄alkyl optionally substituted by 1, 2         or 3 halogen atoms, and R_(6c) is H or C₁₋₄alkyl optionally         substituted by halogen;         each of R_(3c) and R_(4c), independently, is H, C₁₋₄alkyl         optionally substituted by halogen, or acyl, and

-   R_(c) is C₁₃₋₂₀alkyl which may optionally have in the chain an     oxygen atom and which may optionally be substituted by nitro,     halogen, amino, hydroxy or carboxy; or a residue of formula (a)

-   -   wherein R_(7c) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(8c) is         substituted C₁₋₂₀alkanoyl, phenylC₁₋₁₄alkyl wherein the         C₁₋₁₄alkyl is optionally substituted by halogen or OH,         cycloalkylC₁₋₁₄alkoxy or phenylC₁₋₁₄alkoxy wherein the         cycloalkyl or phenyl ring is optionally substituted by halogen,         C₁₋₄alkyl and/or C₁₋₄alkoxy, phenylC₁₋₁₄alkoxy-C₁₋₁₄alkyl,         phenoxyC₁₋₁₄alkoxy or phenoxyC₁₋₁₄alkyl,

-   R_(c) being also a residue of formula (a) wherein R_(8c) is     C₁₋₁₄alkoxy when R_(1c) is C₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl,     or a compound of formula VI

wherein

-   n_(x) is 2, 3 or 4 -   R_(1x) is H; C₁₋₆alkyl optionally substituted by OH, acyl, halogen,     cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl; C₂₋₆alkynyl;     or phenyl optionally substituted by OH; -   R_(2x) is H, C₁₋₄alkyl or acyl -   each of R_(3x) and R_(4x), independently is H, C₁₋₄alkyl optionally     substituted by halogen or acyl, -   R_(5x) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and -   R_(6x) is C₁₋₂₀alkanoyl substituted by cycloalkyl;     cyloalkylC₁₋₁₄alkoxy wherein the cycloalkyl ring is optionally     substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy;     phenylC₁₋₁₄alkoxy wherein the phenyl ring is optionally substituted     by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, -   R_(6x) being also C₄₋₁₄alkoxy when R_(1x) is C₂₋₄alkyl substituted     by OH, or pentyloxy or hexyloxy when R_(1x) is C₁₋₄alkyl, -   provided that R_(ex) is other than phenyl-butylenoxy when either     R_(5x) is H or R_(1x) is methyl,     or a pharmaceutically acceptable salt thereof;     -   Compounds as disclosed in WO02J06268AI, e.g. a compound of         formula VII

wherein each of R_(1d) and R_(2d), independently, is H or an amino-protecting group; R_(3d) is hydrogen, a hydroxy-protecting group or a residue of formula

R_(4d) is lower alkyl; n_(d) is an integer of 1 to 6; X_(d) is ethylene, vinylene, ethynylene, a group having a formula -D-CH₂— (wherein D is carbonyl, —CH(OH)—, O, S or N), aryl or aryl substituted by up to three substitutents selected from group a as defined hereinafter; Y_(d) is single bond, C₁₋₁₀alkylene, C₁₋₁₀alkylene which is substituted by up to three substitutents selected from groups a and b, C₁₋₁₀alkylene having O or S in the middle or end of the carbon chain, or C₁₋₁₀alkylene having O or S in the middle or end of the carbon chain which is substituted by up to three substituents selected from groups a and b; R_(5d) is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl substituted by up to three substituents selected from groups a and b, aryl substituted by up to three substituents selected from groups a and b, or heterocycle substituted by up to three substituents selected from groups a and b; each of R_(6d) and R_(7d), independently, is H or a substituent selected from group a; each of R_(8d) and R_(9d), independently, is H or C₁₋₄alkyl optionally substituted by halogen; <group a> is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino, lower aliphatic acylamino, cyano or nitro; and <group b> is cycloalkyl, aryl, heterocycle, each being optionally substituted by up to three substituents selected from group a; with the proviso that when R_(5d) is hydrogen, Y_(d) is a either a single bond or linear C₁₋₁₀ alkylene, or a pharmacologically acceptable salt or ester thereof;

-   -   Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a         compound of formula VIII:

wherein R_(1e), R_(2e), R_(3e), R_(4e), R_(5e), R_(6e), R_(7e), n_(e), X_(e) and Y_(e) are as disclosed in JP-14316985; or a pharmacologically acceptable salt or ester thereof;

-   -   Compounds as disclosed in WO 03/29184 and WO 03/29205, e.g.         compounds of formula IX

wherein X_(f) is O or S, and R_(1f), R_(2f), R_(3f) and n_(f) are as disclosed in WO 03/29184 and 03/29205, each of R_(4f) and R_(5f), independently is H or a residue of formula

wherein each of R_(8f) and R_(9f), independently, is H or C₁₋₄alkyl optionally substituted by halogen; e.g. 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol or 2-amino-2-[4-(benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propane-diol, or a pharmacological salt thereof.

In each case where citations of patent applications are given, the subject matter relating to the compounds is hereby incorporated into the present application by reference.

Acyl may be a residue R_(y)—CO— wherein R_(y) is C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or phenyl-C₁₋₄alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

When in the compounds of formula I the carbon chain as R₁ is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula I are those wherein R₁ is C₁₃₋₂₀alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R₁ is phenylalkyl substituted by C₆₋₁₄-alkyl chain optionally substituted by halogen and the alkyl moiety is a C₁₋₆alkyl optionally substituted by hydroxy. More preferably, R₁ is phenyl-C₁₋₆alkyl substituted on the phenyl by a straight or branched, preferably straight, C₆₋₁₄alkyl chain. The C₆₋₁₄alkyl chain may be in ortho, meta or para, preferably in para.

Preferably each of R₂ to R₅ is H.

A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1P receptor agonist of formula I is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:

A preferred compound of formula II is the one wherein each of R′₂ to R′₅ is H and m is 4, i.e. 2-amino-2-(2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl)propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g the hydrochloride.

A preferred compound of formula III is the one wherein W is CH₃, each of R″₁ to R″₃ is H, Z₂ is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride. The R-enantiomer is particularly preferred.

A preferred compound of formula IVa is the FTY720-phosphate (R_(2a) is H, R_(3a) is OH, X_(a) is O, R_(1a) and R_(1b) are OH). A preferred compound of formula IVb is the Compound C-phosphate (R_(2a) is H, R_(3b) is OH, X_(a) is O, R_(1a) and R_(1b) are OH, Y_(a) is O and R_(4a) is heptyl). A preferred compound of formula V is Compound B-phosphate.

A preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.

A preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.

When the compounds of formulae I to IX have one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced. Compounds of formula III or IVb, when the carbon atom bearing the amino group is asymmetric, have preferably the R-configuration at this carbon atom.

Examples of pharmaceutically acceptable salts of the compounds of the formulae I to IX include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the methods of the present invention encompass hydrate and solvate forms.

The S1P receptor agonists have, on the basis of observed activity, e.g. homing of lymphocytes, e.g. as described in EP627406A1 or U.S. Pat. No. 6,004,565, been found to be useful e.g. as immunosuppressant, e.g. In the treatment of acute allograft rejection.

It has now been found that S1P receptor agonists have a beneficial effect in heart diseases, e.g. in chronic heart failure, congestive heart failure, complications of cardiovascular surgery, peri-operative hypertension, unstable angina or acute myocardial infarction.

Chronic heart failure is a clinical syndrome characterized by distinctive symptoms and signs resulting from disturbances in cardiac output, e.g. Inadequate for the body's needs. It is often associated with other changes such as cardiac hypertrophy and myocardial ischemia. Congestive heart failure (CHF), or heart failure, is a condition in which the heart cannot pump enough blood to the body's other organs. As blood flow out of the heart slows, blood returning to the heart through the veins backs up, causing congestion in the tissues.

In accordance with the particular findings of the present invention, there is provided:

-   1.1 A method for treating chronic heart failure in a subject in need     thereof comprising administering to said subject a therapeutically     effective amount of a S1P receptor agonist; -   1.2 A method for improving heart energy efficiency and/or reducing     its oxygen needs in a subject in need thereof comprising     administering to said subject a therapeutically effective amount of     a S1P receptor agonist; -   1.3 A method for improving cardiac output in a subject in need     thereof comprising administering to said subject a therapeutically     effective amount of a S1P receptor agonist; -   1.4 A method for treating arrhythmia or tachyarrhythmia, e.g. atrial     fibrillation, atrial flutter or sinus ventricular tachycardia, in a     subject in need thereof comprising administering to said subject a     therapeutically effective amount of a S1P receptor agonist; -   1.5 A method for treating congestive heart failure in a subject in     need thereof comprising administering to said subject a     therapeutically effective amount of a S1P receptor agonist;     -   The method of the invention is also appropriate for patients         with acutely decompensated congestive heart failure and patients         with pre-existing arrythmias. -   1.6 A method for treating complications of cardiovascular surgery,     e.g. peri-operative hypertension, in a subject in need thereof     comprising administering to said subject a therapeutically effective     amount of a S1P receptor agonist; -   1.7 A method for treating unstable angina in a subject in need     thereof comprising administering to said subject a therapeutically     effective amount of a S1P receptor agonist; -   1.8 A method for treating acute myocardial infarction in a subject     in need thereof comprising administering to said subject a     therapeutically effective amount of a S1P receptor agonist. -   2. A S1P receptor agonist, e.g. a compound of formula I or a     pharmaceutically acceptable salt thereof, for use in a method as     defined under 1.1 to 1.8 above; or -   3. A S1P receptor agonist, e.g. a compound of formula I or a     pharmaceutically acceptable salt thereof, for use in the preparation     of a pharmaceutical composition for use in a method as defined under     1.1 to 1.8 above; or -   4. A pharmaceutical composition for use in a method as defined under     1.1 to 1.8 above comprising a S1P receptor agonist, e.g. a compound     of formula I or a pharmaceutically acceptable salt thereof, together     with one or more pharmaceutically acceptable diluents or carriers     therefor.

Utility of the S1P receptor agonists, e.g. in the treatment of heart diseases, as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.

A. Binding Affinity of S1P Receptor Agonists to Individual Human S1P Receptors May be Determined in Following Assays:

Transient Transfection of Human S1P Receptors into HEK293 Cells

S1P receptors and G_(i) proteins are cloned, and equal amounts of 4 cDNAs for the S1P receptor, G_(i-α), G_(i-β) and G_(i-γ) are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method (M. Wigler et al, Cell. 1977; 11; 223 and D S. Im et al., Mol. Pharmacol. 2000; 57; 753). Briefly, a DNA mixture containing 25 μg of DNA and 0.25 M CaCl is added to HEPES-buffered 2 mM Na₂HPO₄. Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12+10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCl₂, 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After centrifugation at 800×g, the supernatant is diluted with HME without sucrose and centrifuged at 100,000×g for 1 h. The resulting pellet is rehomogenized and centrifuged a second hour at 100,000×g. This crude membrane pellet is resuspended in HME with sucrose, aliquoted, and snap-frozen by immersion in liquid nitrogen. The membranes are stored at 70° C. Protein concentration is determined spectroscopically by Bradford protein assay.

GTPγS Binding Assay Using S1P Receptor/HEK293 Membrane Preparations

GTPγS binding experiments are performed as described by D S. Im et al., Mol. Pharmacol. 2000; 57:753. Ligand-mediated GTPγS binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl₂, pH 7.5) using 25 μg of a membrane preparation from transiently transfected HEK293 cells. Ligand is added to membranes in the presence of 10 μM GDP and 0.1 nM [³⁵S]GTPγS (1200 Ci/mmol) and incubated at 30° C. for 30 min. Bound GTPγS is separated from unbound using the Brandel harvester (Gaithersburg, Md.) and counted with a liquid scintillation counter.

B. In Vivo

The effect of a S1P receptor agonist, e.g. a compound of formula I on chronic heart failure is tested in rabbits where heart failure is induced as a consequence of a large myocardial infarction (R P. H of et al. J. Cardiovasc. Pharmacol., 1991, 18, 361-368). The changes of atrial natriuretic factor or baroflex sensitivity are a reliable indicator of the status of the heart failure in this animal model. When administered i.v. at a dose of from 0.1 to 10 mg/kg, a S1P receptor agonist, e.g. the compounds of formula I, e.g. Compound A, have a beneficial effect on the heart failure.

C. Clinical Trial

Patients with class IV congestive heart failure are selected: they have elevated intracardiac filling pressures (orthopnea, abdominal discomfort attributed to hepato-splenic congestion, peripheral edema, ascites, rales and jugular venous distension) and inadequate peripheral perfusion. Patients receive a daily dose of the S1P receptor agonist to be tested, e.g. Compound A in free form or a pharmaceutically acceptable salt thereof, e.g. orally, during 2 or 4 weeks or 3 months. The dose may be escalated if necessary. Patients are followed-up for 6 months. Following data are collected during hospitalization and the 6 month follow-up: blood pressure, weight, electrocardiogram, echocardiogram, serum electrolytes, natriuretic hormone profile and exercise stress tests.

A beneficial effect is observed.

Daily dosages required in practicing the method of the present invention will vary depending upon, for example, the compound used, the host, the mode of administration, the severity of the condition to be treated. A preferred daily dosage range is about from 0.03 to 2.5 mg/kg per day as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from e.g. 0.5 to 50 mg p.o. Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 25 mg active ingredient, e.g. FTY720, e.g. in hydrochloride form, together with one or more pharmaceutically acceptable diluents or carriers therefor. As an alternative, the S1P receptor agonist may also be administered twice or three times a week, e.g. at a dosage as indicated above.

The S1P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions. Pharmaceutical compositions comprising a S1P receptor agonist, e.g. a compound of formula I may be manufactured in conventional manner, e.g. as described in EP-A1-627,406 or in EP-A1-1,002,792.

The S1P receptor agonists may be administered as the sole ingredient or together with other drugs, e.g. an angiotensin converting enzyme inhibitor, e.g. benazepril, captopril, quinapril, ramipril, enalapril, linisopril or moexipril, an angiotensin II receptor antagonist, e.g. valsartan, losartan, irbesartan, eprosartan, forasartan, olmesartan, ripisartan, saprisartan, candesartan, tasosartan or telmisartan, a synthetic form of B-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, e.g. nesiritide, other drugs used in patients with heart failure, e.g. digoxin or digitalis preparations, a β-blocker, e.g. propanolol, atenolol, a β-adrenergic receptor agonist, e.g. salbutamol, an α-2 receptor agonist, e.g. dexmetomidine, a calcium antagonist, e.g. cilnidipine, or a diuretic, e.g. hydrochlorothiazide or spironolactone.

Where the S1P receptor agonists are administered in conjunction with other drugs, dosages of the co-administered compound will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition to be treated, and so forth. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to Include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

In accordance with the foregoing the present invention provides in a yet further aspect:

-   5. A pharmaceutical combination comprising a) a first agent which is     a S1P receptor agonist, e.g. a compound of formula I, e.g. FTY720,     or Compound B or C or a compound of formula V or VIII, or a     phosphate thereof, or a pharmaceutically acceptable salt thereof,     and b) a co-agent, e.g. a second drug agent as defined above. -   6. A method as defined above comprising co-administration, e.g.     concomitantly or in sequence, of a therapeutically effective amount     of a S1P receptor agonist, e.g. a compound of formula I, e.g.     FTY720, or Compound B or C, or a compound of formula V or VIII, or a     phosphate thereof, or a pharmaceutically acceptable salt thereof,     and a second drug substance, e.g. as indicated above.

S1P receptor agonists are well tolerated at dosages required for use in accordance with the present invention. For example, FTY720 has an acute LD₅₀>10 mg/kg p.o. in rats and monkeys.

The administration of a pharmaceutical combination of the invention results in a beneficial effect, e.g. a synergistic therapeutic effect, less side-effects or an improved quality of life compared to a monotherapy. 

1. (canceled)
 2. (canceled)
 3. A pharmaceutical composition for use in the treatment of chronic heart failure, congestive heart failure, arrhythmia or tachyarrhythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output, comprising a S1P receptor agonist together with one or more pharmaceutically acceptable diluents or carriers therefor.
 4. A method for treating chronic heart failure, congestive heart failure, arrhythmia or tachyarrhythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a S1P receptor agonist.
 5. A pharmaceutical combination comprising a) a first agent which is a S1P receptor agonist and b) a co-agent selected from an angiotension converting enzyme inhibitor, an angiotension II receptor antagonist, a synthetic form of B-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, a β-blocker, a β-adrenergic receptor agonist, an α-2 receptor agonist a calcium antagonist and a diuretic.
 6. A method according to claim 4 comprising co-administration concomitantly or in sequence, of a therapeutically effective amount of a S1P receptor agonist and a co-agent selected from an angiotension converting enzyme inhibitor, an angiotension II receptor antagonist, a synthetic form of β-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, a β-blocker, a β-adrenergic receptor agonist, an α-2 receptor agonist a calcium antagonist and a diuretic.
 7. The composition of claim 3, wherein the S1P receptor agonist is selected from a compound formula I

wherein R₁ is a straight- or branched C₁₂₋₂₂carbon chain which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR₆ wherein R₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy, or R₁ is a phenylalkyl wherein alkyl is a straight- or branched (C₆₋₂₀)carbon chain or a phenylalkyl wherein alkyl is a straight- or branched (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by a straight- or branched (C₆₋₂₀)carbon chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkoxy chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by C₆₋₂₀alkyl, heteroarylalkyl substituted by C₆₋₂₀alkyl, heterocyclic C₆₋₂₀alkyl or heterocyclic alkyl substituted by C₆₋₂₀alkyl, and wherein the alkyl moiety may have in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl or NR₆, wherein R₆ is a defined above, and as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R₂, R₃, R₄ and R₅, independently, is H, C₁₋₄alkyl or acyl; a compound of formula II

wherein m is 1 to 9 and each of R′2, R′3, R′4 and R′5, independently, is alkyl or acyl, a compound of formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted or by OH substituted phenyl; R″₄O(CH₂)n; or C₁₋₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p−1) of carbon atoms, e.g. substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, oxo, haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3, each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl; a compound of formula IVa or IVb

wherein X_(a) is O, S, NR_(1s), or a group —(CH₂)_(na)—, which group is unsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s) H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or (C₁₋₄) alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) is independently selected from H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or (C₄₋₁₄)alkenyl; and a: compound of formula V

wherein m_(c) is 1, 2 or 3; X_(c) is O or a direct bond; R_(1c) is H; C1-6alkyl optionally substituted by OH, acyl, halogen, C3-10cycloalkyl, phenyl or hydroxy-phenylene; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted by OH; R_(2c) is

wherein R_(5c) is H or C₁₋₄alkyl optionally substituted by 1, 2 or 3 halogen atoms, and R_(6c) is H or C₁₋₄alkyl optionally substituted by halogen; each of R_(3c) and R_(4c), independently, is H, C₁₋₄alkyl optionally substituted by halogen, or acyl, and R_(c) is C₁₃₋₂₀alkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_(7c) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(8c) is substituted C₁₋₂₀alkanoyl, phenylC₁₋₁₄alkyl wherein the C₁₋₁₄alkyl is optionally substituted by halogen or OH, cycloalkylC₁₋₁₄alkoxy or phenylC₁₋₁₄alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, phenylC₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxyC₁₋₁₄alkoxy or phenoxyC₁₋₁₄alkyl, R_(c) being also a reside of formula (a) wherein R_(8c) is C₁₋₁₄alkoxy when R_(1c) is C₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; or a compound of formula VI

wherein n_(x) is 2, 3 or 4 R_(1x) is H; C₁₋₆alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by OH; R_(2x) is C₁₋₄alkyl or acyl each of R_(3x) and R_(4x), independently, is H, C₁₋₄alkyl optionally substituted by halogen or acyl, R_(5x) is H, C₁₋₄alkyl or C₁₋₄alkoxy and R_(6x) is C₁₋₂₀alkanoyl substituted by cycloalkyl; cycloalkylC₁₋₁₄alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄ alkoxy; phenylC₁₋₁₄alkoxy wherein the phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy; R_(6x) being also C₄₋₁₄alkoxy when R_(1x) is C₂₋₄alkyl substituted by OH, pentyloxy or hexyloxy when R_(1x) is C₁₋₄alkyl, provided that R_(6x) is other than phenyl-butylenoxy when either R_(5x) is H or R_(1x) is methyl, or a pharmaceutically acceptable salt thereof.
 8. The method of claim 4, wherein the S1P receptor agonist is selected from a compound of formula I

wherein R₁ is a straight or branched (C₁₂₋₂₂)carbon chain which may have in the chain a bond or a hetero atom selected tom a double bond, a triple bond, O, S, NR₆, wherein R₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or R₁ is a phenylalkyl wherein alkyl is a straight- or branched (C₆₋₂₀)carbon chain or a phenylalkyl wherein alkyl is a straight- or branched (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by a straight- or branched (C₆₋₂₀)carbon chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkoxy chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by C₆₋₂₀alkyl, heteroarylalkyl substituted by C₆₋₂₀alkyl, heterocyclic C₆₋₂₀alkyl or heterocyclic alkyl substituted by C₆₋₂₀alkyl, and wherein the alkyl moiety may have in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆, wherein R₆ is a defined above, and as a substituted alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R₂, R₃, R₄ and R₅, independently, is H, C₁₋₄alkyl or acyl; a compound of formula II

wherein m is 1 to 9 and each of R′2, R′3, R′4 and R′5, independently, is H, alkyl or acyl, a compound of formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted or by OH substituted phenyl; R″₄O(CH₂)n; or C₁₋₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain acyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p−1) of carbon atoms, e.g.: substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo, haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3, each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl; a compound of formula IVa or IVb

wherein X_(a) is O, S, NR_(1a) or a group —(CH₂)_(na)—, which group is unsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s) is H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or (C₁₋₄) alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) is independently selected from H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen or O(C₁₋₄)alkyl wherein alkyl is unsubstituted substituted by halogen; and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or (C₄₋₁₄)alkenyl; and a compound of formula V

wherein m_(c) is 1, 2 or 3; X_(c) is O or a direct bond; R_(1c) is H; C1-6alkyl optionally substituted by OH, acyl, halogen, C3-10cycloalkyl, phenyl or hydroxy-phenylene; C2-6alkenyl; C2-6alkynyl or phenyl optionally substituted by OH; R_(2c) is

wherein R_(5c) is H or C₁₋₄alkyl optionally substituted by 1, 2 or 3 halogen atoms; and R_(6c) is H or C₁₋₄alkyl optionally substituted by halogen; each of R_(3c) and R_(4c), independently, is H, C₁₋₄alkyl optionally substituted by halogen, or acyl, and R_(c) is C₁₃₋₂₀alkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_(7c) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(8c) is substituted C₁₋₂₀alkanoyl, phenylC₁₋₁₄alkyl wherein the C₁₋₁₄alkyl is optionally substituted by halogen or OH, cycloalkylC₁₋₁₄alkoxy or phenylC₁₋₁₄alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, phenylC₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxyC₁₋₁₄alkoxy or phenoxyC₁₋₁₄alkyl, R_(c) being also a reside of formula (a) wherein R_(8c) is C₁₋₁₄alkoxy when R_(1c) is C₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, or a impound of formula VI

wherein n_(x) is 2, 3 or 4 R_(1x) is H; C₁₋₆alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by OH; R_(2x) is H, C₁₋₄alkyl or acyl each of R_(3x) and R_(4x), independently, is H, C₁₋₄alkyl optionally substituted by halogen or acyl, R_(5x) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(6x) is C₁₋₂₀alkanoyl substituted by cycloalkyl; cyloalkylC₁₋₁₄alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy; phenylC₁₋₄alkoxy wherein the phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, R_(6x) being also C₄₋₁₄alkoxy when R_(1x) is C₂₋₄alkyl substituted by OH, pentyloxy or hexyloxy when R_(1x) is C₁₋₄alkyl, provided that R_(6x) is other than phenyl-butylenoxy when either R_(5x) is H or R_(1x) is methyl, or a pharmaceutically acceptable salt thereof.
 9. The pharmaceutical combination of claim 5, wherein the S1P receptor agonist is selected from a compound of formula I

wherein R₁ is a straight- or branched (C₁₂₋₂₂)carbon chain which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxylamino, hydroxy or carboxy; or R₁ is a phenylalkyl wherein alkyl is a straight- or branched (C₁₋₆)carbon chain or a phenylalkyl wherein alkyl is a straight- or branched (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by a straight- or branched (C₆₋₂₀)carbon chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkoxy chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by C₆₋₂₀alkyl, heteroarylalkyl substituted by C₆₋₂₀alkyl, heterocyclic C₆₋₂₀alkyl or heterocyclic alkyl substituted by C₆₋₂₀alkyl, and wherein the alkyl moiety may have in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆, wherein R₆, is a defined above, and as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy Or carboxy, and each of R₂, R₃, R₄ and R₅, independently, is H, C₁₋₄alkyl or acyl; a compound of formula II

wherein m is 1 to 9 and each of R′2, R′3, R′4 and R′5, independently, is H, alkyl or acyl, a compound of formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted or by OH substituted phenyl; R″₄O(CH₂)n; or C₁₋₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p−1) of carbon atoms, e.g. substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo, haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3; n is 2 or 3, each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl; a compound of formula IVa or IVb

wherein X_(a) is O, S, NR_(1s) or a group —(CH₂)_(na)—, which group is unsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s) is H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or (C₁₋₄) alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) is independently selected from H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or (C₄₋₁₄)alkenyl; and a compound of formula V

wherein m_(c) is 1, 2 or 3; X_(c) is O or a direct bond; R_(1c) is H, C1-6alkyl optionally substituted by OH, acyl, halogen, C3-10cycloalkyl, phenyl or hydroxy-phenylene; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted by OH; R_(2c) is

wherein R_(5c) is H or C₁₋₄alkyl optionally substituted by 1, 2 or 3 halogen atoms, and R_(6c) is H or C₁₋₄alkyl optionally substituted by halogen; each of R_(3c) and R_(4c), independently, is H, C₁₋₄alkyl optionally substituted by halogen, or acyl, and R_(c) is C₁₃₋₂₀alkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_(7c) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(8c) is substituted C₁₋₂₀alkanoyl, phenylC₁₋₁₄alkyl wherein the C₁₋₁₄alkyl is optionally substituted by halogen or OH, cycloalkylC₁₋₁₄alkoxy or phenylC₁₋₁₄alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, phenylC₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxyC₁₋₁₄alkoxy or phenoxyC₁₋₁₄alkyl, R_(c) being also a reside of formula (a) wherein R_(8c) is C₁₋₁₄alkoxy when R_(1c) is C₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, or a compound of formula VI

wherein n_(x) is 2, 3 or 4 R_(1x) is H, C₁₋₆alkyl optionally substituted by OH, acyl, halogen cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by OH; R_(2x) is H, C₁₋₄alkyl or acyl each of R_(3x) and R_(4x), independently, is H, C₁₋₄alkyl optionally substituted by halogen or acyl, R_(5x) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(6x) is C₁₋₂₀alkanoyl substituted by cycloalkyl; cycloalkylC₁₋₁₄alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy; phenylC₁₋₁₄alkoxy wherein the phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, R_(6x) being also C₄₋₁₄alkoxy when R_(1x) is C₂₋₄alkyl substituted by OH, pentyloxy or hexyloxy when R_(1x) is C₁₋₄alkyl, provided that R_(6x) is other than phenyl-butylenoxy when either R_(5x) is H or R_(1x) is methyl, or a pharmaceutically acceptable salt thereof.
 10. The method of claim 6, wherein the S1P receptor agonist is selected from a compound of formula I

wherein R₁ is a straight- or branched (C₁₂₋₂₂)carbon chain which may have in the chain a bend or a hetero atom selected from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy, or R₁ is a phenylalkyl wherein alkyl is a straight- or branched (C₆₋₂₀)carbon chain or a phenylalkyl wherein alkyl is a straight- or branched (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by a straight- or branched (C₆₋₂₀)carbon chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkoxy chain optionally substituted by halogen, a straight- or branched (C₆₋₂₀)alkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by C₆₋₂₀alkyl, heteroarylalkyl substituted by C₆₋₂₀alkyl, heterocyclic C₆₋₂₀alkyl or heterocyclic alkyl substituted by C₆₋₂₀alkyl, and wherein the alkyl moiety may have in the carbon chain, a bond of a heteroatom selected from a double bond, triple bond, O, S, sulfinyl, sulfonyl, or NR₆, wherein R₆ is a defined above, and as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R₂, R₃, R₄ and independently, is H, C₁₋₄alkyl or acyl; a compound of formula II

wherein m is 1 to 9 and each of R′2, R′3, R′4 and R′5, independently, is H, alkyl or acyl, a compound of formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted or by OH substituted phenyl, R″₄O(CH₂)n; or C₁₋₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms, or unsubstituted or substituted straight chain alkoxy having a number (p−1) of carbon atoms, e.g. substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo, haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl and halogen, Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂ is a single bond or straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3, each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl; a compound of formula IVa or IVb

wherein X_(a) is O, S, NR_(1s) or a group —(CH₂)_(na)—, which group is unsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s) is H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or (C₁₋₄)alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) independently selected from H or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or (C₁₋₁₄)alkenyl; and a compound of formula V

wherein m_(c) is 1, 2 or 3; X_(c) is O or a direct bond; R_(1c) is H, C1-6alkyl optionally substituted by OH, acyl, halogen, C3-10cycloalkyl, phenyl or hydroxy-phenylene; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted by OH; R_(2c) is

wherein R_(5c) is H or C₁₋₄alkyl optionally substituted by 1, 2 or 3 halogen atoms, and R_(6c) is H or C₁₋₄alkyl optionally substituted by halogen; each of R_(3c) and R_(4c), independently, is H, C₁₋₄alkyl optionally, substituted by halogen, or acyl, and R_(c) is C₁₃₋₂₀alkyl which may optionally have in the than an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_(7c) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(8c) is substituted C₁₋₂₀alkanoyl, phenylC₁₋₁₄alkyl wherein the C₁₋₁₄alkyl is optionally substituted by halogen or OH, cycloalkylC₁₋₁₄alkoxy or phenylC₁₋₁₄alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, phenylC₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxyC₁₋₁₄alkoxy or phenoxyC₁₋₁₄alkyl, R_(c) being also a reside of formula (a) wherein R_(8c) is C₁₋₁₄alkoxy when R_(1c) is C₁₋₄alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, or a compound of formula VI

wherein n_(x) is 2, 3 or 4 R_(1x) is H; C₁₋₆alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by OH; R_(2x) is H, C₁₋₄alkyl or acyl each of R_(3x) and R_(4x), independently, is H, C₁₋₄alkyl optionally substituted by halogen or acyl, R_(5x) is H, C₁₋₄alkyl or C₁₋₄alkoxy, and R_(6x) is C₁₋₂₀alkanoyl substituted by cycloalkyl; cyloalkylC₁₋₁₄alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy; phenylC₁₋₁₄alkoxy wherein the phenyl ring is optionally substituted by halogen, C₁₋₄alkyl and/or C₁₋₄alkoxy, R_(6x) being also C₄₋₁₄alkoxy when R_(1x) is C₂₋₄alkyl substituted by OH, pentyloxy or hexyloxy when R_(1x) is C₁₋₄alkyl, provided that R_(6x) is other than phenyl-butylenoxy when either R_(5x) is H or R_(1x) is methyl, or a pharmaceutically acceptable salt thereof. 